The field of the invention is gene therapy and cardiac therapy.
It is well known that viruses naturally deliver nucleic acids to cells and have therefore been exploited as gene delivery vehicles. However, in order for a recombinant virus to delivery a nucleic acid to a cell, the virus must first have access to the cell. Circulating virus in a mammal may not have ready access to cells to which it is desired that a nucleic acid be delivered. The present invention provides a means of providing to a virus access to cells to which it is desired that a nucleic acid be delivered.
The recent cloning of full length cDNAs for gene products implicated in several muscular dystrophies (Lim et al., 1995, Nature Genetics 11: 257-265; Piccolo et al., 1995, Nature Genetics, 10: 243-245; Nigro et al., 1996, Nature Genetics 14:195-198; Bonnemann et al., 1995, Nature Genetics 11: 266-273; and Helbling-Leclerc et al., 1995, Nature Genetics 11:216-218) has been paralleled by improvement in a variety of virus-based vector systems for use in somatic gene transfer (Yang et al., 1994, Nature Genetics 7:362-369; Yeh et al. 1996, J. Virology 70: 559-565; and Wilson, 1996, New Eng. J. Med. 334:1185-1187). The universal muscle involvement and resulting respiratory insufficiency in these diseases have focussed attention on the need for systemic vector delivery in vivo to mammal tissues and organs (Boland et al., 1996, Pediatric Neurology, 14: 7-12; Stedman et al., 1991, Nature 352: 536-539; Schlenker et al., 1991, J. Appl. Physiol. 71: 1655-1662; and Smith et al., 1987, New Engl. J. Med. 316: 1197-1205). Under physiologic conditions, the continuous endothelium of the skeletal muscle microvasculature is virtually impermeable to proteins larger than albumin (Stokes radius 3.5 nanometers; Berne et al., 1992, In: Physiology, Mosby, St. Louis), and the underlying basal lamina restricts the diffusion of larger macromolecular aggregates (Majno et al., 1961, J. Biophys. Biochem. Cytol. 11:571-597).
There is an acute need to develop compositions and methods which facilitate access of large macromolecules to muscle for the purposes of delivery of compounds which are of therapeutic benefit to mammals in need of such compounds. The present invention satisfies this need.
Muscular dystrophies and other myopathies are inherited, generally progressive disorders in which non-expression or abnormal expression of a muscular gene causes weakness, hypertrophy, and/or loss of normal muscular control. Many of these disorders have been associated with chromosomal mutations, although some (e.g. mitochondrial myopathies) are instead associated with deletions in mitochondrial DNA. For example, Duchenne muscular dystrophy (DMD) has been associated with mutations in the human gene encoding dystrophin protein.
Although respiratory compromise dominates the clinical course of end-stage DMD, underlying cardiomyopathy is universally present in such DMD patients. In some muscular dystrophies, including those involving dystrophinopathy (e.g. Becker muscular dystrophy) and those involving sarcoglycanopathy (e.g. limb-girdle muscular dystrophy), heart failure severe enough to require transplantation is sometimes observed (Piccolo et al., 1994, Neuromusc. Disord. 4:143-146; Fadic et al., 1996, N. Engl. J. Med. 334:362-366). In addition, at least a dozen other gene products have been implicated in the pathogenesis of recessively inherited dilated cardiomyopathy in humans (Fadic et al., 1996, N. Engl. J. Med. 334:362-366; Piccolo et al., 1995, Nature Genet. 10:243-245; Lim et al., 1995, Nature Genet. 11:257-265; Noguchi et al., 1995, Science 270:819-822; Nigro et al., 1996, Nature Genet. 14:195-198; Nigro et al., 1997, Hum. Mol. Genet. 6:601-607; Bione et al., 1994, Nature Genet. 8:323-327; Taroni et al., 1992, Proc. Nat. Acad. Sci. U.S.A. 89:8429-8433; Witt et al., 1992, J. Neurol. 239:302-306; Ho et al., 1994, Cell 77:869-880; Reichmann et al., 1991, Eur. Heart J. 12(Suppl. D):169-170; Eishi et al., 1985, Hum. Pathol. 16:193-197; Bione et al., 1996, Nature Genet. 12:385-389; Yokoyama et al., 1987, Br. Heart J. 57:296-299; Elleder et al., 1990, Virchows Arch. A Pathol. Anat. Histopathol. 417:449-455; Nagao et al., 1991, Clin. Genet. 39:233-237; Schultheiss et al., 1996, Mol. Cell Biochem. 163-164:319-327).
By way of example, common human cardiac diseases have been reproduced in mice in order to exploit the ability of germline gene transfer to achieve transgene expression in all cardiac myocytes. Two studies by others suggest the potential therapeutic benefit of transgenes expressed in the heart following somatic gene transfer in the adult mammal, provided that gene transfer occurs in a large majority of, or even all, cardiac myocytes. G protein mediated signaling pathways are targeted in both studies, addressing diseases as divergent as cardiac hypertrophy and dilated cardiomyopathy.
In the first study, cDNA encoding a peptide inhibitor of beta adrenergic receptor kinase 1 (bARK1) was expressed under the control of the cardiac muscle-specific alpha myosin heavy chain promoter (Rockman et al., 1998, Proc. Natl. Acad. Sci. USA 95:7000-7005). Breeding of transgenic mice integrating this construct with mice from a recently developed cardiomyopathic line (muscle LIM protein deficient {MLPxe2x88x92/xe2x88x92}) led to the striking finding that the cardiomyopathy was prevented in the offspring. MLPxe2x88x92/xe2x88x92 mice exhibit numerous abnormalities of cardiac myocyte structure and function that resemble those seen in a broad variety of human cardiomyopathies. The transgene-encoded inhibitor prevented these abnormalities through a general mechanism that is not directly coupled to normal functioning of the LIM protein This study indicates that delivery of a similar gene construct to human cardiac tissue could have significant therapeutic benefit for humans afflicted with a wide variety of cardiomyopathies, if only such a gene construct could specifically delivered to human cardiac myocytes with high efficiency.
In the second study, cDNA encoding a peptide inhibitor of binding between cardiac myocyte adrenergic receptors and a protein of the Gq subclass was expressed under the control of the cardiac muscle-specific alpha myosin heavy chain promoter (Akhter et al., 1998, Science 280:574-577). Transgenic mice integrating this construct were subjected to cardiac pressure overload by undergoing surgical transverse aortic constriction. Cardiac overexpression of this inhibitor greatly reduced the cardiac hypertrophic response to pressure overload. Several signal transduction pathways implicated in the human cardiopathological response to cardiac overload were demonstrated to be activated as a result of the surgical procedure. In the setting of strong signal activation, the reduction in cardiac hypertrophy associated with expression of the peptide inhibitor demonstrates that the inhibitor acts at a position common to multiple signal transduction cascades. This study also indicates that delivery of a similar gene construct to human cardiac tissue could have significant therapeutic benefit for humans afflicted with a wide variety of cardiomyopathies, if only such a gene construct could specifically delivered to human cardiac myocytes with high efficiency.
Other cardiac disorders (e.g. heart failure, myocardial infarction, rheumatic fever, arrhythmia, congestive heart failure, infective endocarditis, and pericarditis) are known to be associated with numerous non-congenital causes, but might nonetheless benefit from gene therapy methods if gene vectors comprising a nucleic acid encoding a beneficial gene product could be provided specifically and safely to cardiac tissue.
Unfortunately, the position of the heart within the human body has, in the past, required the use of highly invasive procedures for providing therapy directly and locally to cardiac tissue. In addition to the serious physiological complications which sometimes accompany such highly invasive procedures, these interventions may also exact a high psychological toll from patients who undergo them. These patients endure the physical trauma and long recovery periods associated with invasive cardiac procedures, and often emerge from recovery scarred, both physically and mentally.
Patients afflicted with cardiac and other myopathies are unable to benefit from many of the improvements being made to gene vectors, and from greater understanding of how their afflictions might be alleviated using gene therapy methods, because of a severe paucity of methods for performing local gene therapy in cardiac and other muscle tissues. The present invention provides local muscular gene therapy methods, compositions, kits, and apparatus which satisfy this critical need.
The invention relates to a cardiac isolation catheter which is insertable within the vena cava of a mammal. The catheter comprises
(a) a hollow tubular body having a venous blood flow lumen extending longitudinally therein, a proximal end, a distal end, a proximal port, and a distal port;
(b) a distal vessel seat attached to the body; and
(c) a proximal vessel seat attached to the body.
The catheter is positionable within the vena cava of the mammal such that one vessel seat is positioned in the superior vena cava of the mammal between the right atrium and the junction of the brachiocephalic veins and the other vessel seat is positioned in the inferior vena cava between the right atrium and the hepatic veins. The distal port is located distally with respect to the distal vessel seat. The proximal port is located proximally with respect to the proximal vessel seat. When the catheter is emplaced within the vena cava of the mammal, blood in the junction of the brachiocephalic veins and blood in the hepatic veins is in fluid communication with the venous blood flow lumen by way of the ports.
In one embodiment of the cardiac isolation catheter of the invention, at least one of the distal vessel seat and the proximal vessel seat comprises a raised surface extending circumferentially about the body. By way of example, the vessel seat may comprise a pair of closely-spaced raised surfaces, whereby the vena cava is securely seated at the vessel seat by ensnaring the vena cava between the pair of raised surfaces. Alternately, the vessel seat may comprise a pair of closely-spaced raised surfaces, and the body of the catheter may have a suction lumen extending longitudinally therein and communicating with a suction port situated between the pair of closely-spaced raised surfaces, whereby the vena cava is securely seated at the vessel seat by application of suction to the suction lumen.
In another embodiment, at least one of the distal vessel seat and the proximal vessel seat is expandable. The expandable vessel seat may comprise a balloon attached to the body and having an interior which communicates with an inflation lumen extending longitudinally in the body, whereby the vena cava may be securely seated at the vessel seat by expanding the balloon after positioning the catheter in the vena cava of the mammal. Both of the distal vessel seat and the proximal vessel seat may be balloons attached to the body and having interiors which communicate with the inflation lumen.
In a different embodiment of the cardiac isolation catheter of the invention, the body of the catheter has an access lumen extending longitudinally therein and an access port positioned between the distal vessel seat and the proximal vessel seat. The access port communicates with the access lumen. In this embodiment, the cardiac isolation catheter of claim 8, further comprises a second catheter having a distal end. The second catheter is positionable within the access lumen and can be urged through the access port. The distal end of the second catheter may comprise a curved portion for positioning the distal end of the second catheter within the pulmonary artery of the mammal. For example, the distal end of the second catheter may be adapted to the shape of a human heart. Alternately, or in addition, the distal end of the second catheter may have a deformable portion for positioning the distal end of the second catheter within the pulmonary artery of the mammal. The second catheter may be a wire-wrapped catheter, may comprise a pulmonary balloon at the distal end thereof, and/or may have a pressure relief lumen extending longitudinally therein and a right ventricle pressure relief port in fluid communication with the pressure relief lumen.
In still another embodiment, the cardiac isolation catheter of the invention has a fluid flow lumen extending longitudinally in the body thereof and a right atrium fluid access port located in the body between the distal vessel seat and the proximal vessel seat. The body may have a plurality of right atrium fluid access ports circumferentially arranged about the body.
The cardiac isolation catheter of the invention may further comprise at least one non-invasively detectable marker.
The invention also relates to a surgical kit comprising the cardiac isolation catheter of the invention.
The invention further relates to a kit for isolating the heart of a mammal from the rest of the circulatory system of the mammal. The kit comprises
(a) cardiac isolation catheter of the invention having at least one access lumen extending therein from the proximal thereof;
(b) a second catheter insertable within the access lumen; and
(c) an endoaortic catheter.
The second catheter has a distal portion and an inflation lumen extending longitudinally therein and comprises a balloon on the distal portion thereof. The interior of the balloon of the second catheter is in fluid communication with the inflation lumen of the second catheter. The endoaortic catheter comprises a flexible rod having a distal portion and a distal tip and an aortic vessel seat attached to the distal portion of the flexible rod. The aortic vessel seat may attached to the flexible rod at the distal tip thereof. In one embodiment, the flexible rod is hollow and has an expansion lumen extending longitudinally therein. In this embodiment, the aortic vessel seat comprises a balloon attached to the flexible rod and having an interior which communicates with the expansion lumen, whereby the aorta may be securely seated at the aortic vessel seat by expanding the balloon after positioning the distal portion of the endoaortic catheter in the aorta of the mammal. In another embodiment, the balloon is not located at the distal tip of the flexible body and the flexible body has a liquid access lumen extending longitudinally therein and a liquid access port located on the distal portion of the flexible body. The liquid access port is in fluid communication with the liquid access lumen and is located nearer the distal tip of the flexible body than is the balloon. In yet another embodiment of the kit, the second catheter has a fluid uptake lumen extending longitudinally therein and a fluid uptake port on the distal portion of the second catheter, wherein the fluid uptake port communicates with the fluid uptake lumen.
This kit may further comprise other components such as any one or more of the following:
(d) a cannula for insertion into a femoral artery of the mammal, the cannula having an arterial blood flow lumen extending longitudinally therein;
(e) a pump for withdrawing blood from the venous blood flow lumen of the cardiac isolation catheter and providing blood to the arterial blood flow lumen of the cannula;
(f) a blood oxygenator for oxygenating blood removed from the mammal; and
(g) an azygous vein occluder, such as one selected from the group consisting of a hemostat, a cross clamp, a balloon catheter, and a tourniquet.
The kit may also comprise an inflammatory mediator selected from the group consisting of a vascular permeability-enhancing agent (e.g. histamine) and/or a vasodilating agent (e.g. papaverine).
The invention relates to a composition for delivering a macromolecular assembly to an extravascular tissue of an animal comprising the macromolecular assembly and a vascular permeability-enhancing agent. In one embodiment, the macromolecular assembly is a gene vector. In another embodiment, the vascular permeability-enhancing agent is selected from the group consisting of histamine, acetylcholine, an adenosine nucleotide, arachidonic acid, bradykinin, cyanide, endothelin, endotoxin, interleukin-2, ionophore A23187, nitroprusside, a leukotriene, an oxygen radical, phospholipase, platelet activating factor, protamine, serotonin, tumor necrosis factor, vascular endothelial growth factor, a venom, and a vasoactive amine, and is preferably histamine or vascular endothelial growth factor.
In another aspect of the invention, the composition comprises the macromolecular assembly a vascular permeability-enhancing agent, and a vasodilating agent. In one embodiment, the vasodilating agent is selected from the group consisting of papaverine, nimodipine, hydralazine, nitric oxide, epoprostenol, tolazoline, amrinone, milrinone, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, and an organic nitrate compound, and is preferably papaverine.
In yet another aspect of the invention, the composition comprises the macromolecular assembly a vascular permeability-enhancing agent, and an oxygen-transporting agent.
The invention also provides a kit for providing a macromolecular assembly to an extravascular tissue of an animal. The kit comprises a vascular permeability-enhancing agent and a vasodilating agent. In one embodiment, the kit further comprises the macromolecular assembly. In another embodiment, the macromolecular assembly is a gene vector comprising a human gene selected from the group consisting of a gene encoding dystrophin, a gene encoding eutrophin, a gene encoding a sarcoglycan, and a gene encoding a minidystrophin.
In yet another aspect, the kit comprises a vascular permeability-enhancing agent, a vasodilating agent, and an oxygen-transporting agent.
In a further aspect of the invention, the kit comprises a vascular permeability-enhancing agent, a vasodilating agent, and at least one disposable element of an extracorporeal circulatory support and oxygenation system. In one embodiment, the at least one disposable element is an oxygenator having a hollow body, a liquid inlet in fluid communication with the interior of the body, a liquid outlet in fluid communication with the interior of the body, a gas inlet for providing gas to the interior of a gas chamber, at least one gas-permeable membrane separating the gas chamber from the interior of the body, and a gas outlet for permitting gas to exit from the gas chamber, whereby gas exchange is enabled between a fluid in the interior of the body and a gas in the gas chamber. In another embodiment of the kit comprising an oxygenator, the body is a tube, the gas-permeable membrane comprises polytetrafluoroethylene (PTFE) tubing extending within at least a portion of the tube, and the gas chamber comprises the interior of the PTFE tubing.
The invention further relates to a method of delivering a macromolecular assembly to an extravascular tissue of an animal, preferably a human. The method comprises the steps of providing a vascular permeability-altering agent to a blood vessel associated with the tissue to increase the permeability of the endothelial layer of the vessel and providing the macromolecular assembly to the vessel, whereby the assembly is delivered to the tissue through the endothelial layer of the vessel. In one embodiment of the method, the macromolecular assembly is a gene vector, preferably an adenoviral gene vector. The gene vector preferably comprises a human gene, such as a gene selected from the group consisting of a gene encoding human dystrophin, a gene encoding eutrophin, a gene encoding a sarcoglycan, and a gene encoding a minidystrophin. In another embodiment, the gene vector comprises a promoter/regulatory region operably linked to the human gene, wherein the promoter/enhancer region is selected from the group consisting of a human skeletal muscle creatine phosphokinase promoter/regulatory region, a murine skeletal muscle creatine phosphokinase promoter/regulatory region, a promoter/regulatory region of a gene which is ordinarily expressed in a human skeletal muscle cell, and a human constitutive promoter region.
In another aspect of the invention, the method further comprises the step of providing a vasodilating agent to the vessel.
In another aspect of the invention, the tissue to which the macromolecular assembly is delivered is muscle tissue, preferably striated muscle tissue.
In yet another aspect, the method further comprises the step of increasing the perfusion pressure within the vessel above the normal physiological perfusion pressure after providing the macromolecular assembly to the vessel.
In still another aspect, the method further comprises the step of isolating the vessel from the blood circulatory system of the animal prior to providing the macromolecular assembly to the vessel. In one embodiment, the step of isolating the vessel from the blood circulatory system of the animal is performed prior to providing the vascular permeability-enhancing agent to the vessel. In another embodiment, the method further comprises the step of providing a clearance solution to the vessel after providing the macromolecular assembly to the vessel, the clearance solution being substantially free of the vascular permeability-enhancing agent.
In another aspect, the method further comprises the step of providing an oxygen-transporting agent to the vessel after isolating the vessel from the blood circulatory system.
In yet another aspect, the method further comprises the step of subjecting the animal to extracorporeal circulatory support and oxygenation prior to providing the vascular permeability-enhancing agent.
In still another aspect, the method further comprises the step of occluding the blood supply to the liver of the animal prior to providing the macromolecular assembly.
The invention also relates to a method of delivering a gene vector to an extravascular tissue of an animal, the method comprising the steps of
a) isolating a blood vessel associated with the tissue from the blood circulatory system of the animal;
b) thereafter providing a vasodilating agent to the vessel;
c) thereafter providing a vascular permeability-enhancing agent to the vessel to increase the permeability of the endothelial layer of the vessel;
providing the gene vector to the vessel, whereby the vector is delivered to the tissue through the endothelial layer of the vessel;
increasing the perfusion pressure within the vessel above the normal physiological perfusion pressure; and
providing an oxygen-transporting agent to the vessel; and
d) thereafter providing a clearance solution to the vessel, the clearance solution being substantially free of the vascular permeability-enhancing agent.
The invention further relates to a method of providing a gene vector to substantially all muscle tissues of an animal, the method comprising the steps of
a) subjecting the animal to extracorporeal circulatory support and oxygenation;
b) thereafter providing a vasodilating agent to the blood circulatory system of the animal;
providing a vascular permeability-enhancing agent to the blood circulatory system to increase the permeability of the endothelial layer of the vessels of the blood circulatory system;
providing the gene vector to the blood circulatory system, whereby the vector is delivered to substantially all muscle tissues through the endothelial layer of the vessels of the blood circulatory system; and
increasing the perfusion pressure within the vessel above the normal physiological perfusion pressure.
The invention further relates to a therapeutic gene vector for treating a human afflicted with muscular dystrophy. The therapeutic gene vector comprising a nucleic acid which comprises a promoter operably linked with the coding region of a human gene selected from the group consisting of a dystrophin gene, a eutrophin gene, a sarcoglycan gene, and a minidystrophin gene.
The invention also relates to a caval blood uptake kit. This kit comprises a catheter and a pair of vessel seats attached thereto. The catheter has a pair of venous blood uptake ports in communication with a venous blood flow lumen extending longitudinally within the catheter from the venous blood uptake ports to a proximal portion of the catheter. The catheter is insertable within the vena cava of a mammal. In one embodiment of the kit, the catheter is the cardiac isolation catheter of the invention. In another embodiment, the catheter has a notch in the exterior surface thereof, wherein the notch is adapted to fit the body of a second catheter. In yet another embodiment, the kit further comprises an azygous vein occluder.
The invention also includes another caval blood uptake kit. This kit comprising a pair of catheters. Each catheter has a vessel seat attached thereto and a venous blood uptake ports in communication with a venous blood flow lumen extending longitudinally therein from the venous blood uptake port to a proximal portion of the catheter. Each catheter is insertable within the vena cava of a mammal. In one embodiment, at least one of the catheters has a notch on the outer surface thereof, wherein the notch is adapted to fit the body of a second catheter. The kit may further comprise an azygous vein occluder.
The invention further relates to a method of diverting venous blood flow from the vena cavae of a mammal. This method comprising emplacing a cardiac isolation catheter of the invention within the vena cavae of the mammal. In one embodiment of this method, the venous blood flow lumen of the catheter is in fluid communication with an extracorporeal oxygenating device.
The invention still further relates to a method of diverting venous blood flow from the vena cavae of a mammal, the method comprising emplacing a superior caval return catheter within the superior vena cava of the mammal and emplacing an inferior caval return catheter within the inferior vena cava of the mammal, wherein each of the superior caval return catheter and the inferior caval return catheter comprises
(i) a hollow tubular body having a distal end, a port, and a venous blood uptake lumen extending longitudinally within the body from the port to a proximal portion of the body; and
(ii) a vessel seat attached to the body, wherein the vessel seat is located nearer the distal end of the body than is the port.
The superior caval return catheter is positionable within the superior vena cava of the mammal such that the vessel seat of the superior caval return catheter is positioned between the right atrium and the junction of the of the brachiocephalic veins. The inferior caval return catheter is positionable within the inferior vena cava of the mammal such that the vessel seat of the inferior caval return catheter is positioned between the right atrium and the hepatic veins. When the inferior and superior vena cavae of the mammal are seated against the vessel seats, venous blood flow from the vena cavae of the mammal is diverted into the ports and into the venous blood flow lumens. In one embodiment of this method, the hollow body of at least one of the inferior caval return catheter and the superior caval return catheter has an access lumen extending from the distal tip of the body to the proximal portion of the body. The body of that catheter further comprises at least one penetrable seal disposed within the access lumen for permitting passage of a body through the seal while not permitting flow of venous blood through the access lumen from the distal tip to the proximal portion of the body. For example, the penetrable seal may comprise at least one balloon.
The invention also relates to a method of providing an agent to a single compartment selected from the group consisting of the cardiac circulation of a mammal and the non-cardiac, non-pulmonary circulation of the mammal. This method comprises isolating the cardiac circulation from the non-cardiac, non-pulmonary circulation and providing the agent to the single compartment. In one embodiment of this method, the cardiac circulation is isolated from the non-cardiac, non-pulmonary circulation by
(1) inserting a cardiac isolation catheter of the invention into the vena cavae of the mammal,
(2) seating the vena cavae against the distal and proximal vessel seats,
(3) inserting an endoaortic catheter comprising an aortic vessel seat into the aorta of the mammal, and
(4) seating the aorta against the vessel seat.
The cardiac circulation is thereby isolated from the systemic circulation. The cardiac isolation catheter may be a single catheter having at least two vessel seats or, as described herein, a pair of catheters having at least one vessel seat. In one embodiment of this method, the pulmonary artery of the mammal is also occluded, for example by threading a second catheter comprising an arterial vessel seat through a lumen extending longitudinally within the caval catheter, through an access port located between the vessel seats of the caval catheter, through the right atrium and right ventricle of the mammal""s heart, and into the pulmonary artery of the mammal, and then seating the pulmonary artery against the arterial vessel seat. In another embodiment of this method, the azygous vein of the mammal is also occluded. The agent which is delivered by this method may, for example, be selected from the group consisting of a pharmaceutical composition, a composition comprising an imaging agent, and a gene vector (e.g. an adenovirus vector or an adeno associated vector). According to this method, at least one of the cardiac circulation and the non-cardiac, non-pulmonary circulation may be connected with an extracorporeal oxygenating unit.
The invention also includes a method of providing an apparatus to a venous blood cavity of the heart of a mammal. This method comprises inserting at least one catheter into the vena cavae of the mammal, diverting blood flow from the vena cavae of the mammal, and providing the apparatus to the cavity. The catheter comprises at least two vessel seats positionable within the vena cavae of the mammal and has an access port, an access lumen extending longitudinally within the catheter from the access port to a proximal portion of the catheter, at least two blood uptake ports, and at least one venous blood flow lumen extending longitudinally within the catheter from the ports to the proximal portion of the catheter. Blood flow through the vena cavae is diverted by seating the vena cavae against the vessel seats, whereby venous blood flows from the vena cavae, through the blood uptake ports, and into the venous blood flow lumen. The apparatus is provided to the cavity by passing the apparatus through the access port by way of the access lumen and into the cavity.